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Potential for Dependence on Lisdexamfetamine - In vivo and In vitro Aspects
Yun, Jaesuk,Lee, Kwang-Wook,Eom, Jang-Hyeon,Kim, Young-Hoon,Shin, Jisoon,Han, Kyoungmoon,Park, Hye-Kyung,Kim, Hyung Soo,Cha, Hye Jin The Korean Society of Applied Pharmacology 2017 Biomolecules & Therapeutics(구 응용약물학회지) Vol.25 No.6
Although lisdexamfetamine is used as a recreational drug, little research exists regarding its potential for dependence or its precise mechanisms of action. This study aims to evaluate the psychoactivity and dependence profile of lisdexamfetamine using conditioned place preference and self-administration paradigms in rodents. Additionally, biochemical techniques are used to assess alterations in the dopamine levels in striatal synaptosomes following administration of lisdexamfetamine. Lisdexamfetamine increased both conditioned place preference and self-administration. Moreover, after administration of the lisdexamfetamine, dopamine levels in the striatal synaptosomes were significantly increased. Although some modifications should be made to the analytical methods, performing high performance liquid chromatography studies on synaptosomes can aid in predicting dependence liability when studying new psychoactive substances in the future. Collectively, lisdexamfetamine has potential for dependence possible via dopaminergic pathway.
Synthetic cannabinoid, JWH-030, induces QT prolongation through hERG channel inhibition
Yun, Jaesuk,Yoon, Kyung Sik,Lee, Tac-Hyung,Lee, Hyunjin,Gu, Sun Mi,Song, Yun Jeong,Cha, Hye Jin,Han, Kyoung Moon,Seo, Hyewon,Shin, Jisoon,Park, Hye-Kyung,Kim, Hyung Soo,Kim, Young-Hoon Oxford University Press 2016 Toxicology research Vol.5 No.6
<P>The problem of new psychoactive substance (NPS) abuse, which includes synthetic cannabinoids, is emerging globally, and the cardiotoxicity of these synthetic cannabinoids has not yet been evaluated extensively. In the present study, we investigated the effects of synthetic cannabinoids on the cytotoxicity, human Ether-à-go-go-related gene (hERG) channel, action potential duration (APD), and QT interval. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that JWH-030 was more cytotoxic than JWH-210, JWH-250, and RCS4 in H9c2 cells at 0.1 μM. In addition, the cytotoxicity was associated with its pro-apoptotic effects as evidenced by the increase in caspase-3 levels. We demonstrated that a cannabinoid receptor type 2 (CB2) antagonist, AM630, inhibited JWH-030-induced cytotoxicity, whereas a CB1 antagonist, rimonabant, did not. Furthermore, fluorescence polarization assay showed JWH-030 to block the hERG channel (half-maximal inhibitory concentration, IC50 was 88.36 μM). JWH-030 significantly reduced the APD at 90% repolarization (APD90) in rabbit Purkinje fibers and decreased the left ventricular end diastolic pressure (LVEDP) in Langendorff-perfused Sprague-Dawley (SD) rat hearts at 30 μM. In addition, the electrocardiogram (ECG) measurement revealed that the intravenous injection of JWH-030 (0.5 mg kg<SUP>−1</SUP>) prolonged the QT interval in SD rats. These results suggest that JWH-030 is cytotoxic and its cytotoxicity is mediated by its action on the CB2 receptor; it prolongs the QT interval by regulating ion current channels and APD.</P>
Cardiovascular Safety Pharmacology of Sibutramine
Yun, Jaesuk,Chung, Eunyong,Choi, Ki Hwan,Cho, Dae Hyun,Song, Yun Jeong,Han, Kyoung Moon,Cha, Hey Jin,Shin, Ji Soon,Seong, Won-Keun,Kim, Young-Hoon,Kim, Hyung Soo The Korean Society of Applied Pharmacology 2015 Biomolecules & Therapeutics(구 응용약물학회지) Vol.23 No.4
Sibutramine is an anorectic that has been banned since 2010 due to cardiovascular safety issues. However, counterfeit drugs or slimming products that include sibutramine are still available in the market. It has been reported that illegal sibutramine-contained pharmaceutical products induce cardiovascular crisis. However, the mechanism underlying sibutramine-induced cardiovascular adverse effect has not been fully evaluated yet. In this study, we performed cardiovascular safety pharmacology studies of sibutramine systemically using by hERG channel inhibition, action potential duration, and telemetry assays. Sibutramine inhibited hERG channel current of HEK293 cells with an $IC_{50}$ of $3.92{\mu}M$ in patch clamp assay and increased the heart rate and blood pressure ($76{\Delta}bpm$ in heart rate and $51{\Delta}mmHg$ in blood pressure) in beagle dogs at a dose of 30 mg/kg (per oral), while it shortened action potential duration (at $10{\mu}M$ and $30{\mu}M$, resulted in 15% and 29% decreases in $APD_{50}$, and 9% and 17% decreases in $APD_{90}$, respectively) in the Purkinje fibers of rabbits and had no effects on the QTc interval in beagle dogs. These results suggest that sibutramine has a considerable adverse effect on the cardiovascular system and may contribute to accurate drug safety regulation.
( Jaesuk Yun ),( Sun Mi Gu ),( Tac-hyung Lee ),( Yun Jeong Song ),( Seonhwa Seong ),( Young-hoon Kim ),( Hye Jin Cha ),( Kyoung Moon Han ),( Jisoon Shin ),( Hokyung Oh ),( Kikyung Jung ),( Chiyoung Ah 한국응용약물학회 2017 Biomolecules & Therapeutics(구 응용약물학회지) Vol.25 No.3
Synthetic cannabinoids are one of most abused new psychoactive substances. The recreational use of abused drug has aroused serious concerns about the consequences of these drugs on infection. However, the effects of synthetic cannabinoid on resistance to tetanus toxin are not fully understood yet. In the present study, we aimed to determine if the administration of synthetic cannabinoids increase the susceptibility to tetanus toxin-induced motor behavioral deficit and functional changes in cerebellar neurons in mice. Furthermore, we measured T lymphocytes marker levels, such as CD8 and CD4 which against tetanus toxin. JWH-210 administration decreased expression levels of T cell activators including cluster of differentiation (CD) 3ε, CD3γ, CD74p31, and CD74p41. In addition, we demonstrated that JWH-210 induced motor impairment and decrement of vesicle-associated membrane proteins 2 levels in the cerebellum of mice treated with tetanus toxin. Furthermore, cerebellar glutamatergic neuronal homeostasis was hampered by JWH-210 administration, as evidenced by increased glutamate concentration levels in the cerebellum. These results suggest that JWH-210 may increase the vulnerability to tetanus toxin via the regulation of immune function.
Potential for Dependence on Lisdexamfetamine - In vivo and In vitro Aspects
( Jaesuk Yun ),( Kwang-wook Lee ),( Jang-hyeon Eom ),( Young-hoon Kim ),( Jisoon Shin ),( Kyoungmoon Han ),( Hye-kyung Park ),( Hyung Soo Kim ),( Hye Jin Cha ) 한국응용약물학회 2017 Biomolecules & Therapeutics(구 응용약물학회지) Vol.25 No.6
Although lisdexamfetamine is used as a recreational drug, little research exists regarding its potential for dependence or its precise mechanisms of action. This study aims to evaluate the psychoactivity and dependence profile of lisdexamfetamine using conditioned place preference and self-administration paradigms in rodents. Additionally, biochemical techniques are used to assess alterations in the dopamine levels in striatal synaptosomes following administration of lisdexamfetamine. Lisdexamfetamine increased both conditioned place preference and self-administration. Moreover, after administration of the lisdexamfetamine, dopamine levels in the striatal synaptosomes were significantly increased. Although some modifications should be made to the analytical methods, performing high performance liquid chromatography studies on synaptosomes can aid in predicting dependence liability when studying new psychoactive substances in the future. Collectively, lisdexamfetamine has potential for dependence possible via dopaminergic pathway.
Yun, Jaesuk,Gu, Sun Mi,Lee, Tac-hyung,Song, Yun Jeong,Seong, Seonhwa,Kim, Young-Hoon,Cha, Hye Jin,Han, Kyoung Moon,Shin, Jisoon,Oh, Hokyung,Jung, Kikyung,Ahn, Chiyoung,Park, Hye-Kyung,Kim, Hyung Soo The Korean Society of Applied Pharmacology 2017 Biomolecules & Therapeutics(구 응용약물학회지) Vol.25 No.3
Synthetic cannabinoids are one of most abused new psychoactive substances. The recreational use of abused drug has aroused serious concerns about the consequences of these drugs on infection. However, the effects of synthetic cannabinoid on resistance to tetanus toxin are not fully understood yet. In the present study, we aimed to determine if the administration of synthetic cannabinoids increase the susceptibility to tetanus toxin-induced motor behavioral deficit and functional changes in cerebellar neurons in mice. Furthermore, we measured T lymphocytes marker levels, such as CD8 and CD4 which against tetanus toxin. JWH-210 administration decreased expression levels of T cell activators including cluster of differentiation (CD) $3{\varepsilon}$, $CD3{\gamma}$, CD74p31, and CD74p41. In addition, we demonstrated that JWH-210 induced motor impairment and decrement of vesicle-associated membrane proteins 2 levels in the cerebellum of mice treated with tetanus toxin. Furthermore, cerebellar glutamatergic neuronal homeostasis was hampered by JWH-210 administration, as evidenced by increased glutamate concentration levels in the cerebellum. These results suggest that JWH-210 may increase the vulnerability to tetanus toxin via the regulation of immune function.
Lee, Yun-Hee,Yun, Jaesuk,Jung, Jae-Chul,Oh, Seikwan,Jung, Young-Suk GOVI VERLAG GMBH 2016 PHARMAZIE Vol.71 No.5
<P>A number of some chalcone derivatives possess promising biological properties including anti-inflammation, anti-oxidant, and anti-tumor activity. Although it has been shown that some derivatives of chalcone induce apoptosis in different kinds of cancer cells, the involved mechanism of action is not well defined. The purpose of this study is to investigate the primary target of a benzylideneacetophenone derivative (JC3), which is a synthetic compound derived from the chalcone family, in human cancer, using prostate cancer cells as a working model. Herein, we show that JC3 inhibits proteasomal activity as indicated by both in vitro and in cell-based assays. Especially, the JC3-dimer was more potent than monomer in the aspect of proteasome inhibition, which induced apoptosis significantly in the prostate cancer cells. Owing to the critical roles of the proteasome in the biology of human tumor progression, invasion, and metastasis, these findings give an important clue for the development of novel anti-tumor agents.</P>
윤재석(Jaesuk Yun),윤경식(Kyung Sik Yoon),이용섭(Yong-seop Lee),한경문(Kyoung moon Han),차혜진(Hye Jin Cha),신지순(Jisoon Shin),김영훈(Young-Hoon Kim),박혜경(Hye-Kyung Park),김형수(Hyung Soo Kim) 대한약학회 2017 약학회지 Vol.61 No.2
Narcotics, psychotropic substances, and marihuana are controlled by ‘Act on the control of narcotics, ETC’, ‘the 1961 Single Convention on Narcotic Drugs’, or ‘the 1971 Convention on Psychotropic Substances’. However, the abuse of new psychoactive substances (NPS) is an emerging problem in Korea. According to the United Nations Office on Drugs and Crime (UNODC), about 600 NPS are defined and rapid identification methods for NPS need to be developed. Nevertheless, several counter measures have been enforced in Korea. In the present study, 33 NPS including synthetic cannabinoids, phenethylamines, tryptamines, and aminoindanes were tested using Marquis, Duquenois-Levine, Zwikker, Madelin, and Liebermann reagents. Furthermore, we suggested a coloring test sequence for the preliminary identification of unknown substances.